Organic compounds and processes

ABSTRACT

IN WHICH R2 has the meaning given above, R3 is hydrogen or lower-alkyl and the alkali metal salts of those compounds wherein R is -COOR1 in which R1 is hydrogen. The compounds of the above formulae are anti-inflammatory agents, antiandrogenic agents and central nervous system stimulants.   WHEREIN R is -CHO, -COOR1 or -CH2OR2, in which R1 is hydrogen or methyl and R2 is hydrogen or acyl; X is   This invention relates to novel ring B-secosteroid transformation products, to processes for their preparation and more particularly to compounds embraced by the following formulae:

United States Patent [1919 Nelson [111 3,741,990 [451 June 26, 19 73ORGANIC COMPOUNDS AND PROCESSES [75] Inventor: Norman A. Nelson,Galesburg, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Jan. 7, 1971 [21] Appl. No.: 104,796

Related U.S. Application Data [62] Division of Ser. No. 845,534, July28, 1969, Pat. No.

[52] U.S. Cl..... 260/345.3, 260/343.2 R, 260/3407, 260/340.9, 424/283[51] Int. Cl C07d 7/18 [58] Field of Search 260/3432 R, 345.3, 260/3407,340.9

[56] References Cited UNITED STATES PATENTS 6/1969 Kierstead 260/3433l/1972 Nelson 260/3432 Primary Examiner-John M. Ford Attorney-JohnKekich and Ward F. Nixon [57] ABSTRACT This invention relates to novelring B-secosteroid transformation products, to processes for theirpreparation and more particularly to compounds embraced by the followingformulae;

VIII wherein R is CHO, --COOR, or CH OR in which R is hydrogen or methyland R is hydrogen or acyl; X is in which R has the meaning given above,R is hydrogen or lower-alkyl and the alkali metal salts of thosecompounds wherein R is COOR in which R, is hydrogen. The compounds ofthe above formulae are anti-inflammatory agents, antiandrogenic agentsand central nervous system stimulants.

10 Claims, No Drawings ORGANIC COMPOUNDS AND PROCESSES CROSS REFERENCETO RELATEDAPPLICA- TION I This application is a division of applicationSer. No. 845,534, filed July 28, 1969, now US. Pat. No. 3,634,460.

SUMMARY OF THE INVENTION .art.

DETAILED DESCRIPTION OF THE INVENTION The new compounds and theprocesses for their production are illustratively represented by thefollowing sequence of formulae:

- VII 40 hexane carboxylic,

(III;

. (III:

U til? mli ttllo o 0.

IX VIII wherein X and R have the meanings given herein,-

above; X, is

C --Ra l CH; (ClIzh-CH-Ra CH3 0-(GH,).,

--H, 0 J OCHR and . /OCH2 R -CH i lid-R 0--0 In this application theterm lower-alkyl" means an 7 alkyl radical of l to 6 carbon atomsinclusive such as methyl, ethyl, propyl, butyl, amyl, hexyl and isomericforms thereof. The term acyl" means the acyl radical of an organiccarboxylic acid, preferably a hydrocarbon carboxylic acid of l to 12carbon atoms, inclusive, such as acetic, propionic, butyric, isobutyric,pivalic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic,acrylic, crotonic, hexynoic,'heptynoic, octynoic, cyclobutanecarboxylic,cyclopentene carxoylic, 'cyclodimethylcyclohexanecarboxylic, benzoic,toluic, naphthoic, ethylbenzoic, phenylacetic, naphthaleneacetic,phenylvaleric, cinnamic, phenylpropiolic, phenylpropionic,p-butoxyphenylpropionic, succinic, glutaric, dimethylglutaric, maleic,cyclopentylpropionic acids, and the like. The wavy lines appearing inthe structural formulae indicate the a (alpha) configuration, the B(beta) configuration and mixtures thereof.

The novel compounds of formulae VIII and'IX and the alkali metal saltsthereof of thosecompounds,

wherein R is -CO0R, in which R is hydrogen, are active anti-inflammatoryagents, anti-androgenic agents and central nervous system stimulents. Asanti-inflammatory agents the novel compounds of this invention can beused in dosages of 0.5 l5 mg./kg. in the treatment of gouty arthritis,rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, psori- Iatic arthritis, acute superficial thrombophlebitis and painful shouldersyndromes such as peritendinitis, capsulities, bursitis, and acuteshoulder arthritis as well as contact dermatits, atopic dermatitis,neurodermatitis,

anogenital pruritus, seborrheic dermatitis, and the like,

and for the relief of pain and fever.

The novel compositions also find application in the local treatment ofinflammatory conditionsin animal,

mastitis, a disease of the mammary glands which can be of particularconcern in milk-producing animals such as COWS.

As anti-androgenic agents the novel compounds of this invention can beused in dosages of 0.1-5 mg./kg. for the treatment of acne, hirsutism,prostatic hypertrophy and menstrual disorders.

The compounds of this invention are also active as central nervoussystem agents, useful for modulating the temperament of animals.Compounds can be administered to animals at dosages of about 1 mg./kg.of body weight to produce beneficial responses to environmental stimuliand modulation of temperament.

Suitable solid dosage forms include tablets, pills, cap sules, granules,powders, suppositories, and the like. Advantageously, the pharmaceuticalcarriers for such solid forms include corn starch, lactose, dicalciumphosphate, terra alba (calcium sulfate), talc, stearic acid, magnesiumstearate, and gums. Suitable fluid dosage forms include solutions,suspensions, syrups, and emulsions. Advantageously, the pharmaceuticalcarrier for such fluid forms comprise water, oils, and water-oilemulsions. If desired, suitable dispersing or suspending agents can beincluded, for example, tragacanth, acacia, alginates, dextran, sodiumcarboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gelatin,and

' mixtures thereof. Suitable oils for solutions and wateroil emulsionsinclude cottonseed oil, sesame oil, coconut oil, and peanut oil.

The starting materials for the process of this invention, represented byformula I, above, are either known in the art or can be prepared fromthe corresponding A- compounds by treatment with chloranil in accordancewith procedures well known in the art, for example, Agnello et al. J.Am. Chem. Soc. 82, 4293 (1960). Representative A -compounds which can beconverted to the corresponding N' -compounds of Formula I include, forexample,

1 laand 1 lB-hydroxytestosterone;

1 laand llB-hydroxy-androst-4-ene-3,l7-dione;

llaand llB-hydroxy-androst-4-en-3,l7-dione, l7-

ethylene acetal;

1 laand 1 1B- 1 7-dihydroxy-l 7oz-methyltestosterone;

1 laand l l B-hydroxyprogesterone;

1 lo:- and llB-hydroxyprogesterone, ZO-ethylene aceta];

llaand. 11B,

ethylene ketal;

1 la and l lB-hydroxytestololactone; hydrocortisone,

17,20220,2 l-bismethylenedioxy metal; 1101,1711,2l-trihydroxy-4-pregnene-3,2O-dione,

l7,20:20,2 l -bismethylenedioxy acetal; and the like.

In instances where the l la-hydroxy starting material is not readilyavailable it can be prepared from the corresponding llB-hydroxycompounds by methods well known in the art, for example, the protected 11;?- hydroxy compound is oxidized with chromic acid (Jones reagent) toobtain the corresponding ll-keto l7a-dihydroxyprogesterone,

compound which is then converted to l la-hydroxy by a lithium-ammoniareduction.

In carrying out the process of this invention a A- compound of Formula Iis subjected to an osmium tetroxide-periodate oxidation in accordancewith the procedures disclosed by Pappo et al., J. Org. Chem. 21, 478(1956). The selected A -c ompound (I) in an inert solvent such asdioxane, tetrahydrofuran, 1,2- dimethoxyethane and the like is subjectedto osmium tetroxide and a water soluble salt of periodic acid such assodium periodate, potassium periodate, pyridinium periodate, and thelike (sodium periodate is preferred) to obtain the compounds of FormulaII and III. Although the reaction can-be carried out within a widetemperature range, such as from about 0 C. to about C.; it is preferableto carry out the reaction at about room temperature. About 15 C. toabout 35C. is advantageous.

The compounds of Formula II and III exist in equilibrium in solution;the hemiacetal is the preponderant form and is isolated from solution inaccordance with known procedures, for example by chromatography,crystallization and the like.

The compounds of Formula III thus obtained, are then oxidized byselective oxidation with an exces of activated manganese dioxide in asuitable solvent such as chloroform, ethyl acetate, benzene, acetone,methylene chloride and the like, to obtain the corresponding compound ofFormula IV. The reaction can be carried out within the same temperaturerange as disclosed above for the osmium tetroxideperiodate reaction withabout room temperature being generally preferred. Alternatively, whenthe starting steroid material (I) is an 1 la-hydroxy compound, thecompounds of Formula III obtained therefrom, can be selectively oxidizedwith chromic acid, Jones reagent (a solution of 26.72 g. of chromiumtrioxide in 23 ml. of concentrated sulfuric acid diluted with water to avolume of 100 ml.) is prefered, to obtain the corresponding oxidizedcompounds of Formula IV. When chromic acid is to be used as theoxidizing agent otheroxidizable hydroxy groups present in the startingmaterial (I) should be protected by acyl groups, bismethylenedioxygroups and the like. Either a theoretical amount or an excess of oxidantcan be employed. However, to prevent oxidation of the aldehyde functionwhen an excess is used, the oxidation should be carefully controlled andfollowed, and the excess oxidant should be destroyed as soon as thedesired oxidation is complete. V

The compounds of Formula IV, can then be converted to the othercompounds of this invention in accordance with methods known in the art,for example the hydroxymethyl compounds of Formula V are prepared byreduction of the aldehyde function with sodium borohydride followed byselective oxidation with manganese dioxide of any allylic alcoholsinadvertantly produced.

The compounds of Formula III and IV can be converted to correspondingcarboxylic acids of Formula VI by chromic acid oxidation using an excessof oxidant, Jones reagent is preferred. If compounds III and IV containother oxidizable hydroxy groups they can be protected by conventionalmethods such as acylation a hereinafter described.

The carboxylic acids of Formula VI can be converted to theircorresponding methyl esters (VII) in accordance with known methods forexample by reaction with ethereal diazomethane in a suitable organicsolvent such as tetrahydrofuran, ether, methylene chloride, methanol ormixtures of these solvents. When the reaction is complete, the excessdiazomethane is destroyed with acetic acid and the product isolated byconventional methods. The ethylene acetal groups in the substituent X,",of compounds III, IV, V, VI and VII can be removed by a conventionalaqueous acid hydrolysis in the presence of a cosolvent such as methanol,ethanol, tetrahydrofuran, acetone, acetic acid, dioxane and the like.The acid can be p-toluenesulfonic, methanesulfonic, hydrochloric,sulfuric, formic, acetic or similar acid. It is most convenient toconduct the reaction at room temperature for 1-24 hours, but highertemperatures and shorter reaction times can be used [see DjerassiSteriod Reactions", Holden-Day Inc., San Francisco, 1963, pp. 17-22].The bismethylenedioxy group in the substituent X,, of compounds III, IV,V, VI and VII and substituent X of compounds IX and VIII can be removedby conventional hydrolysis. For example by heating the compound in 50percent aqueous acetic acid on a steam bath for 2-4 hours, or by heatingthe compound with 60 percent aqueous formic acid at 80-l00 for 5-50 min.(see Djerassi, supra, pp. 60-61 Acyl derivatives of the compounds ofthis invention are prepared in accordance with methods commonly used forpreparing steriod acyates, for example by treating the compound inpyridine with excess acid anhydride or acid chloride at about roomtemperature for 1-24 hours, or by heating the selected compound with anacid anhydride in the presence of an alkali earth carbonate such ascalcium carbonate. Acylating agents which can be employed are forexample the anhydrides and chlorides of those acids hereinbefore listed.The excess acylating agent is destroyed by cautious addition of water tothe reaction mixture at 0-10 and the product is then isolated byconventional methods.

Alkali metal salts of the carboxylic acids of Formula V1 are prepared bytreating the selected compounds V1 1 with one equivalent of aqueoussodium hydroxide, so-

dium carbonate, sodium bicarbonate, potassium hydroxide, potassiumcarbonate, or potassium bicarbonate. Cosolvents such as methanol,acetone, tetrahydrofuran and the like can be employed to initiallydissolve the acid or the acid can be extracted into the aqueous basefrom a water immiscible solvent such as ether,

methylene chloride, chloroform, etc. The solution of carboxylic acidsalt is concentrated in vacuo to a small volume and the salt isprecipitated by addition of acetone, or the salt can be isolated byfreeze drying.

The following preparation and examples illustrate the .best modecontemplated by-the inventor for carrying out his invention, but are notto be construed as limiting the scope thereof. Preparation 1 1 111,17B-dihydroxyandrosta-4,6-diene- 3-one A mixture of 60 g. of 1la-hydroxytestosterone, 60 g. of recrystallized (dioxane) chloranil and700 ml. of tbutyl alcohol is stirred under reflux for 60 min., thenconcentrated in vacuo. The residue thus obtained, is dissolved in warmchloroform, washed with dilute potassium hydroxide solution, water,saturated sodium chloride solution, dried by filtration throughanhydrous sodium sulfate and the dried solution is then concentrated invacuo. Trituration of the residue so obtained with acetonitrile gives31.5 g. of 1101,1713- dihyroxyandrosta-4,6-diene-3-one, m.p. 242-244; ananalytical sample crystallized from tetrahydrofuranethyl acetate meltsat 244; A 284 my. (6 26,200); IR and NMR spectra are consistant with theassigned structure.

Anal calcd. for C H O C, 75.46;'I-l, 8.67 Found: C, 75.79; H. 8.77.Preparation 2 1la-hydroxypregna-4,6-diene-3,20- dione I Recrystallizedchloranil.(120 g.) is stirred with 120 g. of 11a-hydroxy-4-pregnene-3,20-dione and 1440 ml. of t-butyl alcohol whileheating at reflux temperature for one hour. The solvent is removed invacuo and percent v/v methyl alcohol in chloroform is added. The organicsolution is washed with potassium hydroxide solution, water and dried.Crystallization from acetonitrile gives 29.6 g. ofl1a-hydroxypregna-4,6-diene- 3,20-dione melting at l58-l60 C.

Example 1 1,2,3 ,5,6a,7,7a,8,9,l0,10a.1 1,1 15,111)-tetradecahy-dro-5,8B-dihydroxy-7a}3,1 la-dimethyl -3-oxobenz[d]indeno[5,6-b]pyran-l lacarboxaldehyde andl,2,3,5,6a,7,7a,8,9,10,l0a,l 1,1 la,llb-tetradecahydro-8B-hydroxy-7afl,l lba-dimethyl- To astirred mixture of72.6 g. (0.24 mole) of 1 101,17- B-dihydroxy-androsta-4,6-diene-3-one,1500 ml. of dioxane, 300 ml. of'water, 60 ml. of pyridine and 4 g. ofosmium tetroxide under a nitrogen atmosphere is added at intervals of 0,1.5 and 3.0 hr. freshly prepared solutions of 34.2 g. (0.16 mole) ofsodium metaperiodate in 120ml. of water. One hour after the lastaddition of periodate, a solution of 51.6 g. (0.24 mole) of sodiumperiodate in 240 ml. concentrate water is added followed by 150 ml. ofdioxane. The mixture is then stirred at room temperature for about 24hours. The reaction mixture is filtered and the collected inorganicprecipitate is washed with diox'ane-absolute ethanol (4:1 The filtrateand washings are combined and concentrated in vacuo until solids beginto precipitate. The concentrated is extracted with two 1 1. portions of20 percent ethanol-chloroform and then hydrogen sulfide is then passedinto the combined organic extracts for about 2 min. The mixture isfiltered through. a pad of Celite (diatomaceous earth) and then a pad ofMagnesol (magnesium silicate) (92 mm. dia. X mm.. high) to give filtrateA. The Magnesol pad is then washed with about 4 l. of 25 percentethanolchloroform to give filtrate B. Concentration of filtrate A invacuo and t'rituration of the residue with acetonitrile gives 30.6 g.(38 percent of the hemiacetal, l,2,3,5- ,6a,7,7a,8,9,l0,10a',l 1,1 la,llb-tetradecahydro-5,8B dihydroxy-7afl,l la-dimethyl-3-oxobenz[d]indeno[5,6-b]pyran-l la-carboxaldehyde, m.p. 236 C. (dec.).

Concentration of filtrate B gives 31 g. of crude residue which isdissolved in 1500 ml. of 15 percent ethanol-chloroform and treated withg. of acti-' vated manganese dioxide. 'The mixture is 'stirred at roomtemperature for about 20 hr. and 200 ml. of ethanol is added. Themixture is filtered and the precipitate washed with about 1 l. of 25percent ethanolchloroform. The filtrate and washings are combined andconcentrated in vacuo to give 24 g. of a residue which ischromatographed on a column prepared from 3 kg. of silica gel wet-packedwith 5 percent ethanolchloroform. Elution of the column with 5 percentethanol-chloroformgives from the first band a residue 7 which ontrituration with acetonitrile yields 1 1.3 g. 14

percent of lactone, l,2,3,5,6a,7,7a,8,9,10,10a,1 1,1 la,- l1b-tetradecahydro-8B hydroxy-7aB, l lba-dimethyl-3,5-dioxobenz[d]indeno-[5,6-b]pyran-l lacarboxaldehyde, m.p. 283 C.(dec.); an analytical sample of the lactone is crystallized fromacetonitrile, m.p. 288 C. (dec.); X 233 mu, (6 8,800), IR, NMR and massspectra support the assigned structure. Anal calcd. for c,,H ,o,: C,68.65; H, 7.28. Found: C, 68.42; H, 7.39.

Example 21,2,3,5,6a,7,7a,8,9,10,10a,11,11a,1lbtetradecahydro-8B-hydroxy-7a/3,1lba-dimethyl-3 ,5- dioxobenz[d]indeno[5,6-b]pyran-1 la-carboxaldehyde Amixture of 18.5 g. of the hemiacetal, from Example 1, above, '1 l. of 10percent absolute ethanolchloroform and 100 g. of activated manganesedioxide is stirred at room temperature for 16 hrs., and then 100 ml. ofabsolute ethanol is added. The mixture is filtered through a pad ofCelite and the collected solids are washed with 20 percentethanol-chloroform (ca. 1 1.). The filtrate and washings are combinedand concentrated in vacuo. Trituration of the residue with acetonitrilegives 10.2 g. of the lactone, 1,2,3,5,6a,7,7a,8,9,10,10a,11,1 1a,1lbtetradecahydro-8fl-hydroxy-7a/3-l lba-dimethyl-3,5-dioxobenz[d]indeno[5,6-b]pyran-l 1acarboxaldehyde, m.p. 283 C. (dec.)and 4 g. with m.p. 280 C. (dec.) are obtained from the mother liquor.Example 3 l,2,3,5,6a,7,7a,8,9,10,10a,1 1,1 1a,11btetradecahydro-8B-hydroxy-7afi,1 lbadimethyl-3,5-dioxobenz[d]indeno[5,6-b]pyran-l lacarboxaldehyde, acetate A mixture of19 g. of the lactone, prepared in Example 2, above, 190 ml. of pyridineand 75 ml. of acetic anhydride is stirred at room temperature for 16 hr., then cooled and the excess acetic anhydride is hydrolyzed by thedropwise addition of water keeping the temperature of the reactionmixture below 10 C. The mixture is then shaken with chloroform andexcess cold dilute hydrochloric acid. The organic layer is separated,washed with dilute potassium hydroxide solution, water, dried andconcentrated in vacuo. Tritura- Example 41,2,3,5,6a,7,7a,8,9,10,10a,l1,1la,11btetradecahydro-8B-hydroxy-7aB, 1lba-dimethyl-S ,5 dioxobenz[d]indeno [5,6-b]pyran-1la-carboxylic acid,acetate 0. I 111 A) 0: cm U To a solution of 6 g. of the product ofExample 3, above, 250 ml. of methylene chloride and 250 ml. of acetoneis added with stirring 10 ml. of Jones reagent [J Org. Chem., 21, 1547(1956)]. The reaction is allowed to proceed for about 30 min. at roomtemperature. The mixture is then diluted with 500 ml. of water andextracted with chloroform (500 ml). The organic layers are combined,Washed with water, dried over sodium sulfate and concentrated in vacuoto give 6 g. of 1,2,3,- 5,6a,7,7a,8,9,l0,10a,1 1,1 la,1lb-tetradccahydro-8B- hydroxy-7aB, 1 lba-dimethyl-3,5-dioxobenz[d]indeno[5,6-b]pyran-1 la-carboxylic acid, acetate, m.p. 305C. (dec.); which is recrystallized from dioxane to give 5.2 g. meltingat 314 C. (dec.), and which after one additional recrystallization has amelting point of 215 C. (dec.); A 231 my. (6 9,950); IR, NMR and massspectra support the structure.

Anal calcd. for C l-1 0 C, 64.60; H, 6,71. Found: C 64.57; H, 6.71.

Example 5 l,2,3,5,6aa,7,7a,8,9,10,l0a,l 1,1 la,l 1btetradecahydro-7afi,llba dimethyl-3,5 dioxobenz[d]indeno[5,6-b]pyran-l la-ca'rboxylic acid,methyl ester, acetate oooir The procedure of Example 4, above, isrepeated through the extraction and concentration steps to give 6.0 g.of crude residual l,2,3,5,6a,7,7a,8,9;10,10a,1 l,- 1 la, 1lb-tetradecahydro-8B-hydroxy-7aB,l lbadimethyl-3,5-dioxobenz[d]indeno[5,6-b]pyran-l lacarboxylic acid, acetate. The 6 g. of the lla-carboxylicacid product thus obtained is dissolved in 700 ml. of tetrahydrofuranand 125 ml. of methanol and treated with excess ethereal diazomethanefor min. The excess diazomethane is destroyed with acetic acid and theresulting mixture is concentrated in vacuo. A chloroform solution of theresidue thus obtained is washed with dilute potassium hydroxidesolution, water, dried over sodium sulfate and concentrated. The residuethus obtained is crystallized from methanol to give 4.4 g. of1,2,3,5,6aB,7,7a,8,9,10,10a,11,lla,11b-

- tetradecahydro-7aB,l 1ba-dimethyl-3,5-

dioxobenz[d]indeno[5,6-b]pyran-l la carboxylic acid, methyl ester,acetate, m.p. 20l202.5 C. and 1.0 g. from a 2nd crop m.p. 197 C.; ananalytical sample from methanol has a melting point of 203-204 C.; A P'231 my. (5 10,450); IR, NMR and mass spectra are in agreement with thestructure. Anal calcd. for C H O C, 65.33; H, 6.98. Found: C, 65,23; H,7.08. Example 6 1,2,6a,7,7a,8,9,l0,10a, 11,11a,11bdodecahydro-8B-hydroxy- 1 1a-( hydroxymethyl)- 7aB,1 lba-dimethylbenz[d]indeno[5,6-b]pyran-3,5-

dione, 8-acetate g To a well-stirred Suspension of 7.48 g. (0.020 mole)of the product of Example 3, above, 120 ml. of methylene chloride and 80ml. of absolute ethanol at 0 is added a solution of 0.38 g. (0.040equiv.) of sodium borohydride in 2 ml. of water and 10 ml. of ethanol.Five minutes later 2.4 g. (0.04 mole) of acetic acid is added dropwiseand the resulting mixture is concentrated in vacuo. Absolute ethanol(100 ml.) is added to the residue and the mixture is concentrated invacuo to remove traces of water. The residue is then dissolved in 40 ml.of absolute ethanol and 360 ml. of chloroform and 40 g. of activatedmanaganese dioxide is added. The mixture is stirred at room temperaturefor 20 hours, 100 ml. of ethanol is added and the solids are removed byfiltration. The solids thus obtained are washed with percentethanol-chloroform until the washings are free of product. Concentrationof the total filtrate in vacuo gives a residue which is chromatographedon a column prepared by wet packing 1.5 kg. of silica gel with 5 percentethanol-chloroform. Elution with the same solvent gives an initial bandof material from which 185 mg. of starting material is obtained (frommethanol) m.p. 285 C. (dec.). The second band of material iscrystallized from acetone-hexanes to give 2.05 g. of1,2,6a,7,7a,8,9,l0,10a,11,11a,11bdodecahydro-8B-hydroxy-lla-(hydroxymethyl 7aB,1 1ba-dimethylbenz[d]indeno[5,6-b]pyran-3,5-dione, S-acetate, m.p 2l2-2l3 C., an additional 2.6

g. of the same product, m.p. 21 l-215.59. C. is recovered from themother liquors. An analytical. sample of the product recrystallized fromethylacetate-hexanes gives l,26a,7,7a,8,9,10,l0a,1 1,1 la, 1lb,-dodecahydro- 8B-hydroxy-l la-(hydroxymethyl )-7aBa,llbadimethylbenz[d]indeno[5,6-b]pyran-3,5-dione, 8- acetate, m.p. 2l3-214C., A 231 mp. (a 10,000); IR, NMR and mass spectra are in agreementwith'the structure. 1

Anal. Calcd. for G T- 0 C, 67.00; H, 7.50. Found: C, 67.23; H, 7.72.Example 7 tetradecahydro-Sa,8B-dihydroxy-7ab,l lba-dimethyl-3-oxobenz{d]indeno[ 5 ,6-b]-pyran-1 lacarboxaldehyde, diacetate and l,2,3,5,6a,7,7a,8,9,10,- l0a,1 1,1 la, 1lb-tetradecahydro-5B,8B-dihydroxy- 7ab,l lba-dimethyl-3-oxobenz[d]indeno[5,6-b]- pyran-l la-carboxaldehyde, diacetate V A mixture of 7 g. ofl,2,3,5,6a,7,7a,8,9,l0,10a,l1,1- la, 11b-tetradecahydro-5,8B-dihydroxy-7 a/3,1ladimethyl-3-oxobenz[d]indeno[5,6-b]pyran-l lacarboxaldehyde fromExample 1, above, ml. of pyridine and 30 mlQof acetic anhydride isstirred overnight at room temperature. The mixture is cooled and 50 ml.of water is added dropwise keeping the temperature of the mixture below5 C. Ten minutes after addition .of the water, the mixture is shakenwith chloroform and excess cold dilute hydrochloric acid. The organiclayer is washed with dilute potassium hydroxide solution and water,dried and concentrated in vacuo to give a mixture of1,2,3,5,6a,7,7a,8,9,10,10a,1 1,1 la,11btetradecahydro-5a,8B-dihydroxy-7ab,1 lba-dimethyl-3-oxobenz[d]indeno[5,6-b]-pyran-l 1acarboxaldehyde, diacetate andl,2,3,5,6a,7,7a,8,9,l0,- l0a,1 1,1 la, 1lb-tetradecahydro-SB,8B-dihydroxy- 7ab,llba-dimethyl-3-oxobenz[d]indeno[5,6-b]-pyran- 1 la-carboxaldehyde,diacetate. The NMR spectrum of the product indicated the presence ofabout 60 percent of the Sa-acetoxy isomer and 40 percent of the 5B-acetoxy isorner. I 7

Example 8 SB-acetyll la-formyll,2,6a,7,7a,8,9,l0,-l0a,1 1,1 la,llb-dodecahydro-5- hydroxy-7abfl,l 1ba dim ethylbenz[d ]indeno[5 ,6-.blpyran-3-one Y i F To a solution of l 87 g. of l lahydroxy-4,6-pregnadiene-3,20-dione in 3.31. of dioxane, 135 ml. ofpyridine and 25 550 ml. of water is added 10 g. of osmium tetroxidefollowed immediately by 425 ml. of a solution of 235 g. of sodium (meta)periodate in 1010 ml. of water. The remainder of the solution is addedin two equal parts. the first addition 1.5 hr. from time zero and thesecond 3 hours from time zero (addition of osmium tetroxide). Anadditional 1 18 g. of sodium (meta) periodate in 500 ml. of water isadded 6 hours after time zero. After stirring overnight at roomtemperature, the solids are removed by filtration. Chloroform is addedto the filtrate and the organic layer is dried by filtration through apad of magnesium sulfate. The filtrate is treated with hydrogen sulfidegas for 10 minutes. Solids are removed by filtration through a pad ofdiatomaceous earth. The filtrate is concentrated to dryness in vacuo.The residue thus obtained is dissolved in 10 percent (v/v) ethanol inchloroform and filtered through a pad of magnesium silicate (Magnesol).Elution with 30 percent (v/v) ethanol in chloroform and concentration ofthe effluent gives 96.2 g. of '8B-acetyl-lla-formyll,2,6a,7,7a,8,9,l0,la,1 1,1la,l1b-dodecahydro-5-hydroxy-7aB,11ba dimethylbenz[d]indeno[5,S-b] pyran-3-one, m.p.2132l5C.; A 232; am, 12,24- 0. The IR, NMR and mass spectra support theassigned structure.

An analytical sample crystallized from acetonitrile gives m.p. 220-225C. (dec.). Anal calcd. for C H O C, 69.97; H, 7.83. Found: C, 70.03; H,7.85. Example 9 SB-acetyl-l laformyl-1,2,6a,7,7a,8,9,10,10a,11,1la,11b-dodecahydro-7aB,l1ba-dimethylbenz[d]indeno[5 ,6-b]-pyran-3,5- dione1,2,6a,7,7a,8,9,l0,l0a,11,11a,11b-dodecahydro-5- hydroxy-7aB,l1ba-dimethylbenz[d]indeno[5,6- b]pyran-3-one in 2.5 l. of percent (v/v)ethanol in chloroform is added 225 g. of activated manganese dioxide.The mixture is stirred at ambient temperature for about 24 hours,filtered and the filtrate concentrated in vacuo. Crystallization fromethyl alcohol gives 60.7 g. of the desired lactone, SB-acetyl-lla-formyldodecahydro7afl, l lba-dimethylbenz[d]indeno[ 5,6-b]-pyran-3,5-dione melting at 239242 C. (dec.); an analytical samplemelts at 241 C. (dec.) and exhibits IR and NMR spectra which are inagreement with the structure.

Anal calcd. for c,.n,.o,= C, 70.36; H, 7.31. 7.31. C, 6- 9.95; H, 7.24.

Example 10 8B-acetyll,2,3,5,6a/3,7,7a,8,9,1 0,10a. 1 1,1 121,11btetradecahydro- 7213.1 lba-dimethyl-3,5-

dioxobenz[d]indeno[ 5,6-b1pyran-l la-carboxylic acid To a solution of 25 g. of SB-acetyl-lla-formyll,2,6a,7,7a,8,9,10,10a,11,1la,1lb-dodecahydro-7a/3,llbd-dimethylbenz[d]indeno [5,6-b]pyran-3,5- dione in 230 ml. ofacetone, and 290 m1. of methylene chloride is added 25 m1. of JonesReagent while maintaining the temperature at about 5 C. The cooling bathis then removed and stirring is continued for about 2 hours. Isopropylalcohol is then added to destroy the excess oxidant. The mixture ispoured into ice water and methylene chloride. The organic layer isremoved, washed with water and dried. Crystallization from ethyl acetategives 16.7 g. of the desired acid,SB-acetyll,2,3,5,6aB,7,7a,8,9,l0,l0a,l 1,1 1a,l1btetradecahydro-7aB,llba-dimethyl-3,5- dioxobenz[d]indeno[5,6-b]pyran 1 la-carboxylic acid,melting at 259 26lC; X 231 mp. (6 10,200); IR and NMR spectra supportthe structure; an analytical sample, crystallized from methanol, is adifferent polymorph and melts at 268-270 C.

Anal calcd. for C I-1 0 C, 67.36; H, 7.00. Found: C, 66.89; H, 7.03.

Example 1 l 1,2,3,5,6a,8,7,7a,8,9,l0,10a,l1,11a,1lbtetradecahydro-7aB,llba-dimethy1-3,5- -dioxobenz[d- ]indeno[5,6-b]pyran-l la-carboxylic acidHOLII/OIL\I b CHO To a cooled (5) suspension of 5 g. of 8B-acetyl-lla-formyl-l,2,6a,7,7a,8,9,l0,l0a,1 l,- 1 1a,] lb-dodecahydro-5-hydroxy7aB-1 lbu dimethylbenz[d]indeno[5,6-b]pyran-3-one in ml. ofacetone and.l50 ml. of methylene chloride is added 10 ml. of Jonesreagent. The coolingbath is removed and stirring continued for 3 hours.The same workup as in Example 10 above is used to afford 3.4 g. ofcrystalline8B-acetyl-1,2,3,5,6aB,7,7a,8,9,10,10a,11,1la,llb-tetradecahydro-7al3,llba-dimethyl-3,5 -dioxobenz[- d]indeno[5,6-b]pyran-l la-carboxylic acid,melting at EBB-acetyl- 25 5-258 C.; infrared and NMR spectra. areidentical (KB-acetylj/ fn I A slight excess of ethereal diazometha'ne isadded with stirring to a mixture of 6 g. of the carboxylic acid preparedin Example ll, above, 100ml. of methylene chloride and 100 ml. of ether.After minutes of reaction time, the excess diaz'omethane is destroyed bythe addition of the few drops of acetic acid and the solvents areremoved in vacuo. A chloroform solution of the residue thus obtained iswashed' with dilute hydrochloric acid, dilute potassium hydroxidesolution and water. The dried solution is concentrated in vacuo and theresidue is crystallized from acetonitrile to give 5.3 g. of 8-B-acetyl-l,2,3,5,6a/3,7,7a,8,9,10,l0a,l 1,1 1a,] 1btetradecahydro-7a/3Jlba-dimethyl-3,5- dioxoben2[d]indeno[5 ,6-b]-pyran-l la-carboxylic acid,methyl ester, m.p. 216-2l7 C.; an analytical sample melted at 2l7-2l8, A230 my. (6 10,300); NMR, IR and mass spectra are in agreement with thestructure. I

Anal calcd. for C H 0 C, 68.02; H, 7.27. Found: C, 68.07; H, 7.31.

Example 13 1,2;3,5,6a,7,7a,8,9,l0,l0a,l1,1la,1lb tetradecahydro-7afl,llba-dimethyl-3,5 ,8-trioxobenz [d]indeno[5,6-b]-pyran-lla-carboxaldehyde To a stirred .mixture of 30.0 g. of 1 1B-hydroxyandrosta-4,6ediene-3,l7-dione, 620 ml. of dioxane, 125 ml. ofwater, 25 ml. of pyridine and 2 g. of osmium tctroxidc, under a nitrogenatomsphere, is added at intervals of 0, l.5 and 3.0 hr. freshly preparedwarm solutions of 14.25 g. of sodium periodate in' 60 ml. of water. Onehour after the last addition, a solution of 21.4 g. of sodium periodatein 90 ml. of water is added followed by 125 ml. of dioxane. The mixtureis then stirred at room temperature for about 20 hours. A. solution of14.25 g. of sodium periodate in 60 ml. of water is added and the mixtureis stirred for an additional period of about 24 hours. The reactionmixture is filtered and the precipitate is washed with about 250 ml. of20 percent ethanol in dioxane. The filtrate and washings are combinedand concentrated in vacuo until solids begin to precipitate. The residueis extracted twice with 500 ml. of 20 percent ethanol in chloroform, andthen hydrogen sulfide is passed into the combined organic extracts for 2minutes. The mixture is filtered through a pad of diatomaceous earth andthen a 1 inch pad of magnesium silicate and'the solids are washed with asolution of 20 percent ethanol in chloroform. The combined filtrate andwashes are concentrated in vacuo and the residue is chromatographed on acolumn prepared by wet-packing 3 kg. of silica gel with 8 percentmethanol in chloroform. Elution of the column with 2-4 percent methanolin chloroform gives two principal bands. Band 1 contains a small amountof unchanged starting material. Band ll gives about 8.5 g. ofa,a,7,7a,8,9,10,l0a,1 1,1 13,1 lb-tetradecahydro-S- hydroxy-7aB,llbB-dimethyl-3,8-

dioxobenz[d]indeno[5,6-b ]pyran-l la-carboxaldehyde which is stirredwith 425ml. of chloroform and 42 g.

ofmanganese dioxide for about 24 hours at which time 100 ml. of absoluteethanol is added and the mixture is filtered. Concentration ofthejfiltrate" in vacuo gives a residue which is chromatographed on acolumn pre- LII pared by wet-packing 1 kg. offsilica get with 2 of 8percent methanol in chloroform. Elution 'of the column with 2.5 4percent methanol in chloroform g i ves three principal bands ofmaterial. Material obtained from the first band is recrystallized fromacetone to give 0.25 g. of l,2,3,5,6,a,7,7a,8,9,10,l0a,l 1,1 1a,llbtetradecahydro-7afi,l lba-dimethyl-3,5 ,8-trioxobenz[d]indeno[5,6-b]pyran-;l lacarboxaldehyde,' m.p. 235237 C.; ananalyticals'ample recrystallized.- from methylene chlorideacetone, meltsat 240--243; A g 243 m#i( ;ll;200'); NMR, IR and mass spectra are. inagreementewith the structure. I I, i Anal calcd. for c d-[ 0 C, 69.07;H, 6,71. Found: C, 69.22 H, 6.63.

I claim:

1. A compound of the formula:

wherein R is hydrogen or acyl, in which acyl is the acyl radical of ahydrocarbon carboxylic acid of from 1 to 12 carbon atoms, inclusive; Xis in which R is hydrogen or acyl as defined above, and R is hydrogen ora lower-alkyl radical .of from 1 to 6 carbon atoms; inclusive.

2.1,2,3,4,5,6a,7,7a,8,9,10,10a,11,11a,11btetradecahydro-5,8B-dihydroxy-7aB,lla-dimethyl-3- v oxobenz[d]indeno[5 ,6-b]pyran- 1 1 a-carboxyladehyde,

tetradecahydro-5B,8B-dihydroxy-7ab,l lba-dimethyl-3oxobenz[d]indeno[5,6-b]-pyran-l lacarboxaldehyde, diacetate, thecompound of claim 1, wherein R is acetylfX is (XL-R:

in which R is acetyl and R is hydrogen.

5. 8B-acetyl-l la-formyll,2,6a,7,7a,8,9,10,10a,l 1,1 1a,b-dodecahydro-5-hydroxy-7afi,l lba-dimethylbenz[d]indeno[ .6- b]pyran-3,5-dione, thecompound of claim 1, wherein R is hydrogen. and X is 6. The process forthe preparation of a compound of the formula:

l HOMTOW/N/XK wherein X is in which R is hydrogen or the acylradical ofa hydrocarbon carboxylic acid of from 1 to 12 carbon atoms, inclusive,and R is hydrogen or a lower-alkyl radical of from 1 to 6 carbon atoms,inclusive, which comprises subjecting a 3-keto-A '-steroid of theformula:

wherein X has the meaning given above to an osmium tetroxide-periodateoxidation reaction.

7. The process of claim 6, wherein the periodate is sodiummetaperiodate.

8. The process of claim 7, for the preparation of 1,2,- 3,5,6a,7,7a,8,9,l0,10a,l 1,1 1a,l lb-tetradecahydro- 5f,8fi-dihydroxy-7afl,lla-dimethyl-S- oxobenz[ d]indeno[5,6-b]pyran-l la-carboxaldehyde,wherein the starting 3-l-:eto-A- steroid is 1 la, 17fi-dihydroxy-androsta-4,6-diene-3-one.

9. The process of claim 7 for the preparation of 8B- acetyl-lla-formyl-l ,2,6a,7,7a,8,9, l0,l0a,l 1,1 1a,]lbdodecahydro-5if-hydroxy-7afi, l lbadimethylbenz[d]indeno[5,6-b]pyran-3 one, wherein the starting 3-keto-A"--steroid islla hydroxy-4,6- pregnadiene-3,2O-dione.

10. The process of claim 7 for the preparation ofa,l.2.3,5,6a.7,7a,8,9,l0.lOa,l 1,1 la,llbtetradecahydro-5f-hydroxy-7aB,l l ba-dimethy1-3,8-dioxobenz[d]indeno]5,6-b]-pyran-l lacarboxaldehyde, wherein the starting3-keto-A- steroid is 1 lB-hydroxyandrosta-4,6-diene-3,l7-dione.

I I I i I

2. 1,2,3,4,5,6a,7,7a,8,9,10,10a,11,11a,11b-tetradecahydro-5 xi , 8 Beta-dihydroxy-7a Beta ,11 Alpha -dimethyl-3-oxobenz(d)indeno(5,6-b)pyran-11Alpha -carboxyladehyde, the compund of claim 1, wherein R4 is acetyl;and X is
 3. 1,2,3,5,6a,7,7a,8,9,10,10a,11,11a,11b-tetradecahydro-5 Alpha, 8 Beta -dihydroxy-7ab,11b Alpha-dimethyl-3-oxobenz(d)indeno(5,6-b)-pyran-11 Alpha -carboxaldehyde,diacetate, the compound of claim 1, wherein R4 is acetyl; X is 4.1,2,3,5,6a,7,7a,8,9,10,10a,11,11a,11b-tetradecahydro-5 Beta , 8 Beta-dihydroxy-7ab,11b Alpha -dimethyl-3-oxobenz(d)indeno(5, 6-b)-pyran-11Alpha -carboxaldehyde, diacetate, the compound of claim 1, wherein R4 isacetyl; X is
 5. 8 Beta -acetyl-11 Alpha-formyl-1,2,6a,7,7a,8,9,10,10a,11, 11a,b-dodecahydro-5 xi -hydroxy-7aBeta ,11b Alpha -dimethylbenz(d)indeno(5,6-b)pyran-3,5-dione, thecompound of claim 1, wherein R4 is hydrogen, and X is
 6. The process forthe preparation of a compound of the formula:
 7. The process of claim 6,wherein the periodate is sodium metaperiodate.
 8. The process of claim7, for the prepaRation of 1,2,3,5,6a,7,7a,8,9,10,10a,11,11a,11b-tetradecahydro-5 xi ,8 Beta -dihydroxy-7a Beta,11 Alpha -dimethyl-3-oxobenz(d)indeno(5,6-b)pyran-11 Alpha-carboxaldehyde, wherein the starting 3-keto- Delta 4,6 steroid is 11Alpha , 17 Beta -dihydroxy-androsta-4,6-diene-3-one.
 9. The process ofclaim 7 for the preparation of 8 Beta -acetyl-11 Alpha-formyl-1,2,6a,7,7a,8,9,10,10a,11,11a,11b-dodecahydro-5 xi -hydroxy-7aBeta ,11b Alpha -dimethylbenz(d)indeno(5,6-b)pyran-3 one, wherein thestarting 3-keto- Delta 4,6-steroid is 11 Alpha-hydroxy-4,6-pregnadiene-3,20-dione.
 10. The process of claim 7 for thepreparation of a,1,2,3,5,6a, 7,7a,8,9,10,10a,11,11a,11b-tetradecahydro-5xi -hydroxy-7a Beta , 11b Alpha-dimethyl-3,8-dioxobenz(d)indeno)5,6-b)-pyran-11 Alpha -carboxaldehyde,wherein the starting 3-keto- Delta 4,6-steroid is 11 Beta-hydroxyandrosta-4,6-diene-3,17-dione.